Work

GLP-1-based combination strategies for weight loss: Multi-target agents and combination therapies

Year: 2026

Type: article

Abstract: The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) represents a major breakthrough in the pharmacotherapy of obesity. However, their single-target mechanism has limitations. In recent years, combination strategies targeting multiple pathways and multiple targets have become a frontier in weight-loss drug development. This review systematically examines GLP-1RA-based combination weight-loss strategies, focusing on the scientific rationale and research progress in two main directions: single-agent multi-target agonists and multi-drug combination therapies. In single-agent multi-target strategies, glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor (GLP-1R/GIPR) dual agonists, glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonists, glucagon-like peptide-1 receptor/amylin receptor (GLP-1R/AMYR) dual agonists, and triple agonists achieve weight loss beyond traditional single agents through synergistic regulation of appetite, energy metabolism, and lipolysis. In multi-drug combination therapy, free combinations offer flexibility, while fixed-dose combinations improve convenience and adherence. These strategies improve weight loss and metabolic outcomes, including hepatic fat and cardiometabolic parameters. In terms of safety, gastrointestinal events are the most common. However, as the number of targets increases and doses escalate, potential risks such as increased heart rate and hypoglycemia warrant attention, with particular consideration for thyroid and muscle safety during long-term use. Future research should focus on optimizing personalized treatment strategies, conducting head-to-head comparisons of agents with different mechanisms, developing oral formulations, and exploring long-term maintenance regimens to advance comprehensive obesity management.

Source: Pharmacological Research

DOI: 10.1016/j.phrs.2026.108331

Authors: Xinyao Wang, Rutao Lin, Qinmei Sun, Xin Xin, Qin Feng

Institutions: Shanghai University of Traditional Chinese Medicine, Shuguang Hospital

Language: English

Topic: Pharmacology and Obesity Treatment

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,130